Multifunctional low-density lipoprotein nanoplatforms

多功能低密度脂蛋白纳米平台

• 批准号: 7245112
• 负责人: GANG ZHENG
• 金额: $ 15万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-12 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7245112
• 关键词: Affinity; Anatomy; Applications Grants; Binding; Biocompatible; Blood Circulation; Cancer Detection; Cells; Cholesterol; Detection; Fluorescent Probes; Folic Acid; Gadolinium DTPA; Gadopentetate Dimeglumine; Goals; Label; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Magnetic Resonance Imaging; Malignant Neoplasms; Modification; Nanostructures; Pathway interactions; Phase; Phospholipids; Photochemotherapy; Resolution; Reticuloendothelial System; Signal Transduction; Solutions; Specificity; Surface; Testing; Toxic effect; apolipoprotein B-100; base; biomaterial compatibility; cancer cell; concept; design; folate-binding protein; imaging probe; immunogenic; monolayer; nanodevice; novel; particle; prototype; receptor binding; scavenger receptor; tumor

DESCRIPTION (provided by applicant): Lipoproteins are naturally-existing nanostructures (8 - 1000 nm) responsible for the transport of cholesterol and other lipids in the blood circulation. Being endogenous carriers, lipoproteins are not immunogenic and escape recognition by the reticuloendothelial system. This project will initiate a broad exploration of lipoprotein particles as diverse and biocompatible nanoplatforms, focusing on low-density lipoprotein (LDL) (22nm) as a prototype. In our multifunctional LDL-based nanoplatform (LBNP) design, the diverse targeting is achieved by conjugating certain tumor-homing molecules to the receptor-binding Lys residues exposed on the apoB-100 surface of LDL. This turns off the LDL receptor (LDLR) binding and redirects the resulting LBNP to cancer cells or tumor vasculature via other cancer signatures. The LBNP multifunctionality is achieved by incorporating near-infrared fluorescent (NIRF)/photodynamic therapy (PDT) agents and magnetic resonance imaging (MRI) probes, respectively, into the LBNP lipid core and on its phospholipids monolayer. Thus, accumulation of the MRI/NIRF probes in target cells provides a facile mechanism for amplification of the MRI/NIRF detectable signal and affords opportunities to combine the strength of both MRI (high resolution/anatomic) and NIRF (high sensitivity), whereas the selective delivery of PDT agents to tumors via these pathways also provides a facile transition between cancer detection and treatment. During the R21 phase of the grant proposal (year 01), proof-of-feasibility of the LBNP concept will be provided by conjugating folic acid to LDL to achieve high affinity toward the folate receptor. In the R33 phase (year 02 to 04), the goal is to demonstrate the binding specificity of LBNP to folate receptors and to bring new functions to the LBNP particles thereby generating two novel folate receptor-targeted nanodevices: NIR dyereconstituted LBNP for NIRF/PDT and Gd-DTPA labeled LBNP for MRI. The key questions that will be tested are: 1) Will the stability of LDL particles be compromised by the proposed LDL modifications? 2) Can folic acid-conjugated LBNP bind to folate receptor specifically without binding to LDLR and/or LDL-scavenger receptor? 3) Can folate receptor binding affinity of LBNP be maximized using the multivalency effect? 4) Can the LBNP payload be high enough to exceed the intracellular MRI detection limit? This approach is expected to generate non-immunogenic multifunctional lipoprotein nanoplatforms, thus providing a solution to common problems associated with most synthetic nanodevices, namely biocompatibility and toxicity issues.

描述（由申请人提供）： 脂蛋白是天然存在的纳米结构（8 - 1000 nm），负责胆固醇和其他脂质在血液循环中的运输。作为内源性载体，脂蛋白没有免疫原性，并且逃避网状内皮系统的识别。该项目将启动脂蛋白颗粒作为多样化和生物相容性纳米平台的广泛探索，重点是低密度脂蛋白（LDL）（22 nm）作为原型。在我们的基于LDL的多功能纳米平台（LBNP）设计中，通过将某些肿瘤归巢分子与暴露在LDL的apoB-100表面上的受体结合Lys残基缀合来实现多样化的靶向。这关闭了LDL受体（LDLR）结合，并通过其他癌症特征将所得LBNP重定向至癌细胞或肿瘤血管系统。LBNP多功能性通过将近红外荧光（NIRF）/光动力疗法（PDT）试剂和磁共振成像（MRI）探针分别掺入LBNP脂质核心和其磷脂单层上来实现。因此，MRI/NIRF探针在靶细胞中的积累提供了用于扩增MRI/NIRF可检测信号的简易机制，并提供了将MRI（高分辨率/解剖学）和NIRF（高灵敏度）两者的强度联合收割机组合的机会，而经由这些途径将PDT试剂选择性递送至肿瘤也提供了癌症检测和治疗之间的简易转换。在拨款提案的R21阶段（01年），LBNP概念的可行性证明将通过将叶酸与LDL结合以实现对叶酸受体的高亲和力来提供。在R33阶段（02年至04年），目标是证明LBNP与叶酸受体的结合特异性，并为LBNP颗粒带来新的功能，从而产生两种新型叶酸受体靶向纳米器件：用于NIRF/PDT的NIR染料重构LBNP和用于MRI的Gd-DTPA标记LBNP。将要测试的关键问题是：1）LDL颗粒的稳定性是否会受到拟议LDL修饰的影响？2)叶酸偶联的LBNP能否特异性结合叶酸受体而不结合LDLR和/或LDL-清道夫受体？3)LBNP的叶酸受体结合亲和力能否利用多价效应最大化？4)LBNP的有效载荷是否高到足以超过细胞内MRI检测极限？这种方法有望产生非免疫原性多功能脂蛋白纳米平台，从而为大多数合成纳米器件相关的常见问题（即生物相容性和毒性问题）提供解决方案。